9beta, 19-cyclo steroids of the pregnane and androstane series



United States Patent 3,250,765 9,3,19-CYCLO STEROIDS OF THE PREGNANE ANDANDROSTANE SERIES Oskar Jeger and Kurt Schatfner, Zurich, Switzerland,assignors to Ciba Corporation, New York, N.Y., a corporation of DelawareNo Drawing. Filed Oct. 1, 1962, Ser. No. 227,594 Claims priority,application Switzerland, Oct. 3, 1961, 11,475/ 61 27 Claims. (Cl.260239.55)

This invention relates to 95:19-cyclosteroids and to a process for thepreparation thereof. These compounds, in particular 9fizl9-cyclosteroidsof the pregnane series and androstane series, are pharmacologicallyeffective and are also advantageous intermediate products for themanufacture of other biologically active steroids. Thus,3:20-dioxo-9,8:19-cyclopregnane compounds and their substiution productshave an effect on the mineral metabolism in that they have asodium-eliminating action. 21- unsubstituted pregnane derivatives, suchas, for example, A I):11:20-trioxo-9B:19-cyclopregnene, moreover have aprogestational effect. A -3-oxo-9fl:19-cycloandrostenes which areoxygenated in 17-position and also the corresponding saturated compoundsare of interest in particular as anabolics. 3 :20-dioxo-9fi:19-cyclopregnane derivatives which are hydroxylated at the 21 and/ orthe 17 carbon atom are also anti inflammatory and effective asanti-shock agents.

The 9,8219-cyclo structure has heretofore been found in nature only inthe triterpene series. Thus, for example, in the case of the pentacycliccycloartenol, it is a question of A 96:19-cyclolanostene. Access tothese products by synthetic methods, however, is unkown.

It has now been found that 913:19-cyclosteroids can be obtained byesterifying 19-hydroxysteroids having an oxo group in ll-position or adouble bond in 9(11)-positio'n with a sulfonic acid, treating the estersobtained with basic agents and, if desired, removing the ll-oxo group orhydrogenating the 11:12-double bond, in a manner known per se, in thell-oxoor A -9B:19-cyclo compounds formed and, if required, forming a A-3-oxo group in the ring A.

To convert the 19-hydroxysteroids used as starting materials into thecorresponding 19-sulfonic acid esters, aliphatic, for example loweraliphatic sulfonic acids are employed in particular such as, forinstance, methanesulfonic acid, ethanesulfonic or monocyclic aromaticsulfonic acids, such as, for example, p-toluenesulfonic acid,pbromobenzene-sulfonic acid, etc., preferably in the form of theirfunctional derivatives, such as, for instance, their halides, especiallythe chlorides. The reaction with these agents is carried out in asuitable organic solvent, preferably in the presence of an organic basesuch as pyridine.

To cyclize the sulfonic acid esters of the 19-hydroxysteroids obtainedaccording to this process so as to form the 95:19-cyclosteroids, thereare used as basic agents, for example, alkali metal and alkaline earthmetal hydroxides, such as, for instance, sodium, potassium, barium orcalcium hydroxide, alakali metal and alkaline earth metal carbonates,such as, for example, lithium carbonate, sodium carbonate, etc., andfurthermore tertiary organic bases such as pyridine, trimethylamine,N-methylpiperidine, etc. Particularly suitable are alkali metalalcoholates of lower aliphatic alcohols, for example, those having 1 to8 carbon atoms, such as, for example methanol, ethanol, tert. butanol,etc. The reaction i preferably carried out in organic solvents, such aslower aliphatic alcohols like those mentioned above and organic basessuch as pyridine, if required, at elevated temperature.

Cyclization is efiected particularly easily in the 19- sulfonic acidesters of A -19-hydroxysteroids. This cyclization, for example, alreadyoccurs at room temperature under the influence of the bases, such as,for instance, pyridine, which may have been employed in theesterifiaction stage.

The 19-hydroxy-1l-oxosteroids employed as starting materials may beprepared by the method described in copending application Ser. No.211,103, filed July 19, 1962, by Oskar Jeger et al., now Patent No.3,147,251. This consists in that 19-unsubstituted ll-oxosteroids areexposed to ultraviolet light and the 11-hydroxy-11:19-cyclosteroidsformed are treated with lead tetraacetate, and

in any resulting 11-oxo-19-acyloxy steroid the acyloxy group ishydrolyzed. Another method of access to the said starting materialsstarting from suitably substituted cardanolides occurring in nature isdescribed in US. Patents Nos. 2,975,173 and 2,976,284. The A -19-hydroxy-steroids likewise employed as starting materials are preferablyobtained from the above-mentioned l9- hydroxy-l l-oxo compounds byreduction with complex metallic hydrides of aluminum or boron, forexample lithium aluminum hydride, sodium boron hydride, lithium orsodium tritertiary butoxy aluminum hydride, followed by partialacetylation in l9-position, splitting off of the 11,6-hydroxyl groupwith formation of the 9(11)-double bond and subsequent hydrolysis of the19-esters.

Particularly suitable as starting materials for the present process are11-oxoor A -l9-hydroxy-steroids of the androstane, pregnane, cholane,cholestane, spirostane, and cardanolide series, as well as triterpenes,for example, of the lanostane type. These may also have furthersubstituents, for example in one or more of positions 1, 2, 3, 4, 5, 6,7, 14, 15, 16, 17, 20, 21 and possibly also in the side chains, such as,for example, alkyl, for instance lower alkyl, groups such as methylgroups or unsaturated a1i phatic hydrocarbon radicals such as, forinstance, ethinyl groups, free or protected, i.e., esterified oretherified hydroxyl groups, free or functionally modified keto groups,such as, for instance, ketals, enamines, enol others, etc., and halogenatoms. Moreover, the compounds may also have one or more double bonds,for example in the 7 in which X signifies hydrogen atoms or a ketogroup.-

The first products of the process as obtained directly by I cyclizationare the 9B: l9-cyclosteroids having a keto group in ll-posi tion or adouble bond in 11:12-position. The products which are unsubstituted inll-position and saturated in the ring C can be obtained for example byreduction with hydrazine and alkali according to the Wolff- Kishnermethod from the ll-keto-9B: l9-cyclosteroids or by catalytichydrogenation, e.g., with palladium catalysts from the h-9fizl9-cyclosteroids. Specific products according to this process are,for example, S-hydroxy- 11:20-dioxo-9B: l9-cyclopregnane, 3 :20diethylenedioxylll-oxo-9 8:l9-cyclopregnane, A -3:11:20-trioxo 9/3119-cyclopregnene, A -3-hydroxy-ll-oxo 9 8: 19 cyclolanostene, A-3-hydroxy-2G-oxo 95:19 cyclopregnene, A 3 :20-diethylenedioxy-9fi:l9-cyclopregnene, A -3 l7-dihydroxy-9B:19-cycloandrostene and theirderivatives saturated in 11: l2-position and functional derivatives ofthew compounds, such as esters, ethers, ketals, etc. In the esters, theacid radicals are preferably those of saturated and unsaturatedaliphatic or cy-cloaliphatic carboxylic acids or of aromatic ofheterocyclic carboxylic acids or acids of mixed type such as araliphaticacids, preferably having ttrorn 1 to 20 carbon atoms, particularly oftrimethylacetic acid and also of acetic acid, propionic acid, butyricacids, valeric acids, such as n-valeric acid, caproic acids, such as,S-trimethylpropionic acid, oenanthic, caprylic, pelargonic, capric,undecyl acids, for example undecylenic acid, lauric, myristic, palmiticor stearic acids, for example oleic acid, cyclopropyl-, cyclobutyl-,cyclopentyland cyclohexyl-carboxylic acid, cyclopropylmethylcanboxylicacid, cyclobutylmethylcarboxylic acid, cyclopentylethylcanboxylic acid,cyclohexylethylcarboxylic acid, cyclpentyl-,

cyclohexylor phenylacetic acids or -propionic acids, benzoic acid,phenoxyalkane acids, such as phcnoxyacetic acid, p-chlorophenoxyaceticacid, 2:4-dichlorophenoxyacetic acid, 4-tert. butylphenoxyacetic acid,3-phenoxypropionic acid, 4-phenoxy-butyric acid, furan-Z-carboxylicacid, -tert. butyl-furan-Z-carboxylic acid, 5-bromofuran- Z-carboxylicacid and nicotinic acids, or the acid radicals are those of,B-keto-carboxylic acids, for example acetoaoetic, propionylacetic,butyrylacetic or capn'noylacetic acid, of amino acids, such asdicthylaminoacetic acid, aspart-ic acid, of dicarboxylic acids, forexample oxalic, succinic, maleic, glutaric, di-methylglutaric, pimeli-c,acetodicarboxylic, acetylenedic-ar-boxylic, phthalic,tetrahydrophthalic, hexahydrophthalic, endomethylenetetrahydro phthalic,endomethylenehexahydrophthalic, endoxyhexahydrophthalic,endoxytetrahydrophthalic acid, camphoric acid, cyclopropanedicarboxylicacid, cyclobutanedicar- 'boxylic acid, diglycollic acid,ethylenebisglycollic acid, polyethylenebisglycollic acids,'thioglycollic acid, furandi carboxylic, dihydrofurandicarboxylic andtetrahydrofurandicarboxylic acids, quinolic acid, cinchomeronic acid andof the polyethyleneglycolmonoalkylether semi-esters of the abovedicar-boxylic acids. Instead of carboxylic acid radicals, radicals ofsulfonic acid and furthermore of phos phoric, sulfuric or hydrohalicacids may also be present.

The conversion of the 3-oxygenated products of this process which aresaturated in 4:5-position into the corresponding A-3-oxo-9fi:19-cyc1osteroids can be efi'ected in a manner known per so bybromination of the 3-oxo compound followed by splitting oil of hydrogenhalide, preferably by heating with lithium halides in an N-dialkylamide,in particular dimethylforrnamide.

Particularly valuable products of the process are, e.g., those of theFormulae I and II Bil/Wis wherein R stands for 0X0, lower alkenedioxy,hydrogen and 'hydroxy, or hydrogen and acyloxy, R for hydrogen or oxo, Rfor 0x0, lower alkylenedioxy, hydrogen and 8- positioned hydroxy oracyloxy or lower alkyl, alkenyl or alkinyl and fi-positioned hydroxy oracyloxy, X for hydrogen, methyl, fluorine or chlorine, R for 0x0 orlower alkylenedioxy, and R and R for hydrogen, hydroxy or acyloxy, andthe dehydro compounds thereof which have a double bond extending fromcarbon atom 5 and/or'in 1l(12)-position. The acyloxy groups are derived,e.g., from the aforementioned acids, especially from carboxylic acidshaving l-20 carbon atoms.

The active substance obtainable by this process can be employed asmedicaments, for example in the form of mixtures of substances whichcontain the said active substance and a solid or liquid excipient. Themixtures of substances are prepared by methods known per 'se, forexample using pharmaceutical, organic or inorganic carrier materialssuitable for parenteral, enteral or local administration. Substanceswhich can be used are substances which do not react with the newcompounds, such as, for example, water, vegetable oils, benzyl alcohols,polyethylene glycols, gela-tines, lactose, starch, magnesium stearate,talc, petroleum jelly, cholesterol or other carrier for medicaments. Inparticular, preparations for parenteral administration are made,preferably solutions, primarily aqueous or oily solutions, and alsosuspensions, emulsions or implants; for enteral application, tablets ordragees arc also prepared, and for local application, moreover,ointments or creams. If required, it is possible to sterilise thepreparations or add auxiliary substances, such as preerving,stabilizing, wetting or emulsifying agents, salts for regulating theosmotic pressure or butters They may also contain other therapeuticallyeffective compounds. The preparation thereof is carried out in knownmanner.

The process is described in detail in the following illustrativeexamples. The ltempemaitures are given in degrees centigrade.

Example 1 1105, 1070, 1055, 1033 cm." (CHCl The product is 3:20-diethylenedioxy-1 1-oxo-19-mesyloxy-5a-pregnane.

Example 2 70 mg. of 3:ZO-diethylenedioxy-ll-oxo-19-mesyloxy- Sa-pIegnaneare heated for 3 hours to 140 C. together with mg. of sodium methylatein 10 ml. of absolute methanol in a bomb tube. The ether extract of thereaction solution is washed with water until neutral and dried overanhydrous sodium sulfate and, after evaporation in'vacuo, yields 70 mg.of oily crystals. Filtration thereof in methylene chloride solutionthrough neutral aluminum oxide (act. II) yields 40 mg. of crystalswhich, after being twice dissolved in acetone-petroleum ether andallowed to crystallize, give a constant melting point of 144 C.Absorption spectrum (ethanol): A 216 m (6=4400). Nuclear magneticresonance spectrum (22 mg. in 0.4 ml. CCl 6:0.75 (doublet, I about 0.8c.p.s.); 1.22 (singlet), 2.79 (doublet, J=15 c.p.s.) and 3.85 p.p.m.(singlet) The product obtained is 3:20-diethylenedioxy-l 1-oxo-95:19-cyclo-5a-pregnane Example 3 1.85 grams of sodium are dissolved in 90m1. of diethyleneglycol under heat and 60 m1. of anhydrous hydrazine and475 mg. of 3:20 diethy1enedioxy-11-oxo-9,8:19-cyclo- 5a-pregnane areadded at 20 C. to the solution. The mixture is first heated for 3 hoursto 130 C. Hydrazine is then distilled off until the temperature of themixture rises to 180 C. and the latter is then allowed to continue toreact at this temperature overnight. Some. hydrazine is thereupondistilled ofi once more and the mixture is heated to 210 C. for another24 hours. The cooled reaction mixture is taken up in ether, washed withwater until neutral and dried over anhydrous sodium sulfate.

fter evaporation of the solution, 430 mg. of crude 3:20-diethylenedioxy-9/3:19-cyclo-5a-pregnane are obtained.

Example 4 A solution of 80 mg. of 3:ZO-diethylenedioxy-l1-oxo-19-hydroxy-5a-pregnane in 5 ml. of absolute ether is add ed dropwise to100 mg. of lithium aluminum hydride dissolved in 10 ml. of absoluteether and the reaction mixture is heated for 1% hours at refluxtemperature while stirring. The excess reducing agent in the cooledreaction mixture is destroyed by adding ethyl acetate and the mixture isthereupon extracted with ether. The organic phase, washed with wateruntil neutral and dried over anhydrous sodium sulfate, yields 80 mg. ofan oily crystalline mixture after evaporation in vacuo. When thismixture is crystallized twice from acetone-petroleum ether, crystals areobtained which have a constant melting point of 212 C. [a] =+32(c=0.704). IR spectrum (CHCl bands at 3580 cm.- The product obtained is3 :20-diethy1enedioxy-11fl: 19-dihydroxy-5a-pregnane.

Example 5 450 mg. of 3:20-diethylenedioxy-l1B:l9-dihydroxy-5apregnaneare dissolved in 8 ml. of acetic anhydride-pyridine mixture (1:1) andallowed to stand for 1% hours at room temperature. The reaction mixtureis thereupon taken up in ether and the solution is washed with wateruntil neutral. The ethereal phase, dried over anhydrous sodium sulfate,yields after evaporation 500 mg. of crude product which ischromatographed on neutral aluminum oxide (activity 11) 250 mg. ofcrystals of 3:20-diethylenedioxy-l lfi-hydroxy-l9-acetoxy-5a-pregnanecan be eluted with benzene-ether mixture (4:1) and these,after beingcrystallized once from acetone-petroleum ether, have a constant meltingpoint of 154 C. (175 mg.). [otJ =+56.2 (:0.873). IR spectrum (CHCl bandsat 3500, 1725 and 1245 cm.

Example 6 2.5 grams of phosphorus oxychloride are added to a solution of140 mg. of 3:20-diethylenedioxy-1lfi-hydroxy- 19-acetoxy-5a-pregnane inml. of pyridine and the mixture is heated for 2 hours to 70 C. Thecooled mixture is thereupon poured onto ice and extracted with ether.The ether solution is washed with sodium hydrogen carbonate solution andwater and dried over anhydrous sodium sulfate. After evaporation thereare obtained 125 mg. of oily A-3:20-diethylenedioxy-19-acetoxy-5otpregnene which shows a yellowreaction with tetranitromethane and exhibits bands at 1720 and 1250 cm?in the IR spectrum (CHCl 6 Example 7 120 mg. of oily and not furtherpurified A -3 :20-diethylenedioxy-l9-acetoxy-5a-pregnene are saponifiedfor one hour at boiling heat in 10 ml. of 5% methanolic potassiumhydroxide solution. After cooling, the mixture is extracted with etherand the organic phase is washed with water until neutral. The ethersolution, dried over anhydrous sodium sulfate, yields after evaporationmg. of crystals which are filtered in a benzene-ether solution (4: 1)through neutral aluminum oxide (activity 11) and, after beingcrystallized once from acetone-petroleum ether, have a constant meltingpoint of 120 C. (58 mg). [a] '=+35 (c=0.627). Nuclear magnetic resonancespectrum (37 mg. in CDCl;;): 5=about 5.44 (wide signal), 3.92 (singlet),3.66 (singlet), 1.30 (singlet) and 0.71 p.p.m. (singlet). The productobtained is A 3 20-diethylenedioxy-19-hydroxy-5a-pregnene.

Example 8 0.15 ml. of mesyl chloride is added to a solution of mg. of A-3:20-diethylenedioxy-19 hydroxy-5apregnene in 5 ml. of pyridine at 0 C.and the mixture is thereupon allowed to stand for 5 minutes whilecooling with ice and for 2% hours at 20 C. The mixture is thereupondiluted with 20 ml. of ether and poured on to ice. After standing forsome time at room temperature, extraction with ether is carried out andthe organic phase is washed with dilute hydrochloric acid, sodiumcarbonate solution and water. The ether solution, dried over anhydroussodium sulfate, gives after evaporation mg. of residue which isrecrystallized from ether-hexane and yields pure A-3z20-diethylenedioxy-9fl: 19-cyclo-5a-pregnene.

Example 9 Hydrogenation of 50 mg. of A -3:20 diethylenedioxy9fizl9-cyclo-5wpregnene in 10 ml. of ethanol in the presence of 50 mg.of palladium carbon yields, after evaporation of the solution, fromwhich the catalyst has been removed, and crystallization, 30 mg. of apreparation which .is identical with 3z20 diethylenedioxy-9l3:19-cyclo-5a-pregnane.

By heating the product obtained with acetic acid of 67% strength for 15minutes to 90 C., dilution with water, filtering 0E, washing the residuewith water, drying and recrystallization from acetone-hexane, 3220-dioxo-Qfi:l9-cyclo-5ot-pregnane is obtained. A 4:5- double bond can beintroduced into this compound in a manner known per se by brominationand dehydrobromination and in this way A -3 :20-dioxo-9,8:19-cyclo-pregnene is obtained.

What is claimed is:

1. Process for the manufacture of 9/8219-cyclosteroids selected from thegroup consisting of androstanes, pregnanes, cholanes, cholestanes,spirostanes, cardanolides and lanostanes, which comprises esterifying acorresponding 19-hydroxysteroid.having in ll-position a member selectedfrom the group consisting of an oxo group and a A -double bond, with asulfonic acid and treating the 19-sulfonic acid ester obtained with abasic agent.

2. Process as claimed in claim 1, wherein the esterification of the19-hydroxy-steroid is performed with a halide of a. lower aliphaticsulfonic acid, in the presence of a tertiary organic base.

3. Process as claimed in claim 1, wherein the esterification of the19-hydroxy-steroid is performed with a halide of a monocyclic aromaticsulfonic acid, in the presence of a tertiary organic base.

4. Process according to claim 1, wherein the esterification of the19-hydroxy-steroid is performed with methane sulfonic acid chloride inthe presence of pyridine.

5. Process according to claim 1, wherein there are used as startingsteroids A -19-hydroxysteroids, the esterification is carried out with asulfonic acid halide in the presence of a basejand the so formed A-9fiz19- cyclosteroids are isolated directly.

6. Process according to claim 1,. wherein the 19-sulfonic acid estersare treated with a member selected from the group consisting of analkali hydroxide, an .alkali alcoholate and alkali carbonate.

7. Process for the manufacture of 9,8: l9-cyclo-steroids, wherein M-913:l9-cyclo-steroids are catalytically hydrogenated to yield thecorresponding 95: l9-cyclo-steroids saturated in 11:12-position.

8. Process for the manufacture of 9,3: l9-cyclo-steroids wherein11-ox0-9fl:l9-cyclo-steroids are treated with hydrazine and alkali toafiord the 9fi:l9-cyclo-steroids unsubstituted in ll-position.

9. A member selected from the group consisting of compounds of theformulae Rjjjm wherein R stands for a member selected from the groupconsisting of x0, lower alkylenedioxy, hydrogen together with hydroxy,hydrogen together with acyloxy, R for a member selected from the groupconsisting of hydrogen and 0x0, R for a member selected from the groupconsisting of 0x0, lower alkylenedioxy, hydrogen together withfi-positioned hydroxyl and hydrogen together with ti-positioned acyloxy,fl-positioned hydroxyl to- 8 I gether with a member selected from thegroup consisting of lower alkyl, lower alkenyl and lower alkinyl, andsuch groupings wherein the ,G-hydroxyl group is esterified, X is amember selected from the group consisting of hydrogen, methyl, fluorineand chlorine, R is a member selected from the group consisting of oxoand lower alkylenedioxy, and R and R are a member selected from thegroup consisting of hydrogen, hydroxy and acyloxy, the dehydro compoundsthereof which have a double bond extending from carbon atom 5, and the Adehydro derivatives of all these compounds unsubstituted in thell-position, the above mentioned esterified hydroxyl groups beingderived from acids having from 1 to 20 carbon atoms.

10. 3:20-dioXo-9B:l9-cyclo5a-pregnane. Y

11. The 3:20 bisethyleneglycol ketal of the compound of claim 10. I

13. 3 11 :20'-tr ioxo-9,8: 19-cyclo-5a-pregnane.

14. The 3:20-bisethyleneglycol ketal of the compound of claim 13.

15. A -3: l1 :20-trioxo-9B: 19-cyclo-pregnene. 16. A -3 20-diOX0-9 3Z19-cyclo-5 a-pregnene.

17. The 3:20-bisethyleneglycol ketal of the compound I 25. A-3:20-dioXo-9B: l9-cyclo-pregnadiene.

26. A -3zl7fi-dihydroxy 17a methyl 913: 19 cycloandrostene. V

27. A -3-oxo-l7fl-hydroxyl7m-methyl :19-cycloandrostadiene.

Refrenc'esCited by the Examiner Wehrli et al.: Helv. Chim. Acta, 44,2162-73 (1961).

LEWIS GOTTS, Primary Examiner.

9. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULAE